A Pathologically Friendly Strategy for Determining the Organ-specific Spatial Tumor Microenvironment Topology in Lung...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Lung cancer exhibits heterogeneous organ-specific responses to immunotherapy.
• Understanding the tumor microenvironment (TME) is crucial for deciphering these divergent responses.
• Challenges in single-cell profiling of formalin-fixed paraffin-embedded (FFPE) materials hinder TME dissection.

Purpose of the Study:

• To dissect the organ-specific cellular and spatial TME in lung adenocarcinoma (LUAD) using FFPE samples.
• To reveal divergent immune niches and cellular neighborhoods across primary LUAD and its metastases.
• To identify mechanisms underlying differential immunotherapy responses in LUAD.

Main Methods:

• Single-cell nuclei RNA sequencing of 84,294 cells.
• Imaging mass cytometry (IMC) on 250,600 cells.
• Analysis of paired primary LUAD and metastatic FFPE samples.

Main Results:

• Divergent organ-specific immune niches were identified.
• Immunotherapy-responsive sites (primary LUAD, adrenal metastases) showed enrichment of B, plasma, and T cells.
• Immunosuppressive sites (brain, liver metastases) displayed collagen I deposition and T cells expressing TIM-3.
• Spatial proximity of B and CD4+ T cells was observed at immunogenic sites.
• Organ-specific densities of tertiary lymphoid structures were detected.

Conclusions:

• This study provides a comprehensive single-cell landscape of the organ-specific TME in LUAD at both cellular and spatial levels.
• Findings highlight the necessity for organ-specific treatment approaches in lung adenocarcinoma.
• The characterized TME features offer insights into immunotherapy resistance and response mechanisms.